Z-endoxifen shows promise in patients with endocrine-refractory metastatic breast cancer

In patients with endocrine-refractory metastatic breast cancer, Z-endoxifen—a tamoxifen metabolite with potent anti-estrogenic activity—provides substantial drug exposure that is unaffected by CYP2D6 metabolism, as well antitumor activity and an acceptable toxicity, according to results from a first-in-human, phase 1 study published in the Journal of Clinical Oncology.

“Tamoxifen is converted into endoxifen in the liver by an enzyme called CYP2D6. Our previous research found that tamoxifen may be less effective in women with poor CYP2D6 metabolism,” said lead author Matthew Goetz, MD, oncologist, Mayo Clinic, Rochester, MN.

In laboratory studies, researchers had previously shown that endoxifen is superior to tamoxifen in inhibiting tumor growth. Partnering with researchers from the National Cancer Institute, Dr. Goetz and colleagues developed Z-endoxifen, an experimental drug that is not affected by CYP2D6 metabolism.

Dr. Goetz and colleagues conducted this study to assess the toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity of Z-endoxifen. They used an accelerated titration schedule until moderate or dose-limiting toxicity occurred, followed by a 3+3 design, and expansion at 40, 80, and 100 mg/d.

In all, 38 patients were evaluable for MTD. Patients were given endoxifen once daily at seven doses, ranging from 20 to 160 mg. Dose escalation stopped at 160 mg/d due to lack of MTD, and endoxifen concentrations greater than 1,900 ng/mL.

They found that CYP2D6 genotype did not affect endoxifen clearance. One patient treated with the 60-mg dose had cycle 1 dose-limiting toxicity due to pulmonary embolus.

Overall, the clinical benefit rate, defined as stability at greater than 6 months (n=7) or partial response by RECIST criteria (n=3) was 26.3% (95% CI: 13.4% to 43.1%), including previous tamoxifen progression in three patients.

Thirteen patients (8 PIK3CA, 5 ESR1, 4 TP53, and 1 AKT) exhibited cell-free DNA (cfDNA) mutations, and had shorter progression-free survival compared with those without cfDNA mutations (median: 61 vs 132 days, respectively; log-rank P=0.046).

Clinical benefit was seen in those with ESR1 amplification (tumor; 80 mg/d) and ESR1 mutation (cfDNA; 160 mg/d). When comparing tumor biopsies and cfDNA, some mutations were undetected, including PIK3CA, TP53, and AKT. In comparing biopsies, cfDNA mutations ESR1, TP53, and AKT were undetected.

“The primary goal of the study was to safely deliver therapeutic levels of endoxifen without the requirement for CYP2D6 liver metabolism,” said Dr. Goetz. “However, one of the most surprising observations was the prolonged anticancer benefit, [which] in some cases lasted more than 2 years in women who had progressed on standard anti-estrogen therapies.”

In another randomized trial (A11203), Dr. Goetz and investigators with the Alliance for Clinical Trials in Oncology and the National Cancer Institute, compared tamoxifen with Z-endoxifen, and their results are expected in 2018.

“We are encouraged by these results and [are] hopeful that, based on these data and ongoing studies, Z-endoxifen could become a new US Food and Drug Administration-approved treatment for women with estrogen-positive metastatic breast cancer,” Dr. Goetz concluded.